Vedolizumab: Potential Mechanisms of Action for Reducing Pathological Inflammation in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC), and Crohn’s disease (CD), are a group of disorders characterized by chronic, relapsing, and remitting, or progressive inflammation along the gastrointestinal tract. IBD is accompanied by massive infiltration of circulating leukocytes into the intestinal mucosa. Leukocytes such as neutrophils, monocytes, and T-cells are recruited to the affected site, exacerbating inflammation and causing tissue damage. Current treatments used to block inflammation in IBD include aminosalicylates, corticosteroids, immunosuppressants, and biologics. The first successful biologic, which revolutionized IBD treatment, targeted the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Infliximab, adalimumab, and other anti-TNF antibodies neutralize TNFα, preventing interactions with its receptors and reducing the inflammatory response. However, up to 40% of people with IBD become unresponsive to anti-TNFα therapy. Thus, more recent biologics have been designed to block leukocyte trafficking to the inflamed intestine by targeting integrins and adhesins. For example, natalizumab targets the α4 chain of integrin heterodimers, α4β1 and α4β7, on leukocytes. However, binding of α4β1 is associated with increased risk for developing progressive multifocal leukoencephalopathy, an often-fatal disease, and thus, it is not used to treat IBD. To target leukocyte infiltration without this life-threatening complication, vedolizumab was developed. Vedolizumab specifically targets the α4β7 integrin and was approved to treat IBD based on the presumption that it would block T-cell recruitment to the intestine. Though vedolizumab is an effective treatment for IBD, some studies suggest that it may not block T-cell recruitment to the intestine and its mechanism(s) of action remain unclear. Vedolizumab may reduce inflammation by blocking recruitment of T-cells, or pro-inflammatory monocytes and dendritic cells to the intestine, and/or vedolizumab may lead to changes in the programming of innate and acquired immune cells dampening down inflammation.

Real‐world data on switching from intravenous to subcutaneous vedolizumab treatment in patients with inflammatory bowel disease

“…In addition, it is possible that the altered pharmacokinetics that comes with SC administration affect the various mechanisms of action of vedolizumab (i.e. those suggested to take place in the circulation compared to within tissues) in different ways 1–3 . Although the VISIBLE studies gave us an indication as to what serum levels are common with SC vedolizumab at standard dose, the studies did not address which levels are therapeutically optimal.…”

“…those suggested to take place in the circulation compared to within tissues) in different ways. [1][2][3] Although the VISIBLE studies gave us an indication as to what serum levels are common with SC vedolizumab at standard dose, the studies did not address which levels are therapeutically optimal. In our study, serum vedolizumab trough concentrations at steady state were approximately twice as high during SC as compared with IV treatment.…”

“…1 This infiltration is facilitated by the interaction between the integrin α4β7, which is expressed on several circulating immune cell subsets including previously activated T-cells, and its counterreceptor Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), which is selectively expressed on the endothelial cells of intestinal venules. 1 Vedolizumab is a humanised monoclonal IgG1 antibody that binds to α4β7 and inhibits the interaction with MAdCAM-1. This prevents α4β7-expressing immune cells from extravasating which leads to a decrease in local inflammatory activity.…”

“…The inflammatory process of Crohn's disease (CD) or ulcerative colitis (UC), which are the two main forms of inflammatory bowel disease (IBD), is thought to be driven by the infiltration of dysregulated proinflammatory immune cells into the inflamed intestinal tissue. 1 This infiltration is facilitated by the interaction between the integrin α4β7, which is expressed on several circulating immune cell subsets including previously activated T-cells, and its counterreceptor Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), which is selectively expressed on the endothelial cells of intestinal venules. 1 Vedolizumab is a humanised monoclonal IgG1 antibody that binds to α4β7 and inhibits the interaction with MAdCAM-1.…”

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

“…On the other hand, α4β7 is the main integrin involved in ulcerative colitis and Crohn’s disease. It is substantiated by evidence that anti-α4β7 antibodies (Vedolizumab, Millennium Pharmaceuticals) can prevent T cells binding to MAdCAM-1 in the mucosal vasculature and thus were approved by the FDA for use in ulcerative colitis and Crohn’s disease in 2014 [ 14 , 15 ]. The major side effects from using systemic anti-integrin therapies are progressive multifocal leukoencephalopathy (PML) and reactivation of John Cunningham (JC) virus infection, which are both serious and potentially fatal [ 14 , 16 ].…”